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lMAI2001;3:783-786

(jThe Israel Society for Research on Magnesium in Biology andMedicine: Proceedings of the First Meeting

Gustawa Stendig-Lindberg MD LRCPIFRSM

Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv University, Israel

Key words: magnesium, physiology, cardiovascular system, therapeutics

The first meeting of the Israel Society forMagnesium Research in Biology andMedicine was held at Tel Aviv Universityon 6/une 2000. Thegoal of the Societyisnot only to encourage magnesium re-search but also to increase awareness ofthe importance of prevention, earlydiagnosis and adequate treatment ofMg deficiencystates. It hopes to createa consensus on the national laboratoryreference interval for Mg, the optimaldaily food Mg requirement, and thechoice of the optimal Mg vehicles to beused in therapeutics.

In a brief review, Dr. Stendig-Lindberghighlighted some salient points on therole of magnesium in biology andmedicine. On removal of Mg from itscentral position in the chlorophyll mo-lecule, photosynthesis ceases, whichillustrates the importance of this ele-ment to life on earth. The basic biologi-cal functions of Mg are twofold: a) itbinds to substrates, enzymes and cellconstituents, servingas a biologicalglue11L and b) it activates enzymes bycombining with the enzyme, the sub-strate, or both, by affectinga conforma-tional change of the enzymeprotein, orby changing the concentration of thesubstrate in an enzymatic reaction. Thefundamental intracellular processesregulated by magnesium are listed onTable 1. In Mg-deficient states, theintracellularchanges include a decreaseof MgH, K+, inorganic phosphate andthe energy-richphosphagenes ATP,ADPand Pc. At the same time there is anincrease in intracellular Na+, cr, CaH

Mg = magnesium

and cAMPactivity, as well as an increasein the interstitial H2O content 121.Magnesium deficiency, which is detri-mental to health and in its severe formis

incompatible with life, is highly preva-lent in Israel, among others, because ofthe high level of stress (increase incatecholaminesinduces Mg diuresis)and the high ambient temperature(causing profuse loss of Mg in sweat).Mg deficiencyis especially common insusceptiblepopulation groups that havean increased Mg requirement, such asadolescents, pregnant and lactating wo-men, and workersand soldiers exposedto strenuous effort and/or high ambienttemperature 13.41.Unfortunately,the Mgdaily food content in Israel of 200-300mg, similar to that of other westerndiets, is inadequate and does not meeteven the "normal" Mg requirement. Itfalls short of the United States Recom-mended DailyAllowanceof 350-420mgper day,whichin addition allowsa dailymagnesium supplement of 350 mg,

giving a totar of 700-770 mg daily.Balance studies, however, indicate aneven higher requirement, e.g., adoles-cents require 1,050mg magnesium perday 151.The Mg deficiency may bemanifest, Le., the serum Mg concentra-tion lies below the lowerborder of thereference interval of 0.82-1.06 mmol/Lfound in a steady state (Le.,in a state ofsaturation of metabolism when all thebody compartments are filled with Mg).Alternatively,the Mg deficiencymay bemanifest, characterized by fluctuatingS-Mgvalues signifyingthe presence ofintracellular Mg deficit. The degree ofintracellularMgdeficitcan be gauged bymeans of the Mg retention test: thegreater the amount of the Lv. adminis-tered Mg retained, the greater theintracellular deficiency.However,sincethe procedure is cumbersome,. it isadvisableto estimate the 24hour urinaryMg content instead. Since the 24 hour

S-Mg = serum magnesium concentration

Table 1. Intracellular processes regulated by magnesium

. Intermediary (fat and carbohydrate) metabolism, protein and nucleic acid metabolism. Energy production (oxidative phosphorylation, glycolysis) and energy consumption(active transport, muscle contraction). The voluntary contraction force of the skeletal muscle. The basic tone of smooth muscle including the smooth muscle of the arteries (including those

of the coronary arteries). The contraction force of the cardiac muscle. The influx and efflux of electrolytes, including that of calcium.Receptorbinding .. Boneturnover. Neuromuscular transmission. The stability/permeability of cell membrane. The correct replication of the genetic code

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U-Mg value is significantly correlated tointracellular Mgcontent 16,71,it shows,inMgdeficiency,a progressivedecreasedueto Mgconservationbythe kidney.Conse-quently, two estimates of S-Mg at anintervalof 7-10 daysand one estimateof24 hour U-Mgwill aid in diagnosing Mgdeficiency, which is often missed -maskedby a seemingly"normal" S-Mg.

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Mg in Cell Physiology

Magnesium ions in the function ofexcitable tissue was the subject of Or.Rahamimoff's presentation. Mg ionshave a profound effect on almost everyexcitable tissue in the body.Among thevarious effects of Mg ions, Prof. Raha-mimoff focused on two aspects ofsynaptic transmission: the effectsof Mgions on transmitter release and the

effect of Mg ions on post-synapticfunction. Quantal releaseof transmitter

from pre-synaptic nerve endings is ofparamount importance in synapticcom-munication among nerve cells. The keyelement in the quantal liberation oftransmitter is the fusion of the synapticvesiclewith the surfacem<;!mbrane.Thisfusion process is triggered by the entryof calcium ions into the surface mem-

brane of the pre-synaptic vesicle. Mgions competewith Ca in this processoftransmitter release and thus play animportant. role in the regulation oftransmitter liberation. Since transmitter

liberation is of importance also insynaptic plasticity, Mg ion is one of themajor participants in this complicatedactivity of neuronal communication.Glutamate ions are the main excitatorytransmitter in the nervous system.Glu-tamate is released from pre-synapticnerve terminals and affects different

post-synaptic receptors. Some of thesereceptorsare directly activatedby gluta-mate, but other receptors(NMDArecep-tors) are partially blockedby magnesiumions; thus a depolarization is necessaryto relieve this magnesiumblock of thepost-synaptic receptors. Thus, magne-sium ions are part of a comprehensiveorchestra of ion channels regulating

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U-Mg = 24 hour urinary magnesiumconcentration

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784 G. Stendig-Lindberg

post-synaptic excitability and transmis-sion properties of excitatorysynapsesinthe brain. It is noteworthy that theblockage of ion channels by Mg ionsplaysa pivotal role in the function of theheart.Oneof the important ion channelsthat stabilizesthe function of the heart is

the inward rectifier. While directing thepotential of heart cells, this inwardrectifier is wide open and stabilizes themembrane,preventing the generationofextra-systoleand arrhythmia. Upon de-polarizationthis channelclosesand thusfacilitates the generation of the actionpotential and heart contraction. Theclosure of this channel is achieved in

part by Mg ions.Thus,Mg deficiencycancause life-threatening cardiac arrhyth-mias by the lack of the blockadeof thisinward rectifierpotassiumchannel in theheart.

Mechanical properties of humanerythrocytes regulated byintracellular Mg

Reporting on his experimental work, Dr.Korenstein discussed the central role

played by the mechanicalproperties ofcirculating blood cells in microcircula-tion. However,exploring the regulationof its mechanical characteristics byphysiological effectors, such as hor-mones,has beenvery limited. Moreover,in view of the fact that the main functionof oxygenatedRBCsis to deliver oxygento respiring cells of the body, thepossibility that deoxygenationof normalhuman RBCs alters their mechanical

properties has scarcelybeen addressed.Initial support for the possible regulatoryeffect of oxygen on the mechanicalproperties of normal human RBCsemergesfrom the previous study whereRBCs subjected to cyclic oxygenationand deoxygenationrevealeda reversibledecreasein the amplitude of submicronmechanical fluctuations of the cellmembrane. These fluctuations, whichreflect the bending deformability of themembrane-skeleton,were monitored bytime-dependent light scattering from asmall area(-0.25 11m2)of the cell surface

RBCs = red blood cells

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by a method based on "point dark fieldmicroscopy." Since one of the mainchanges accompanying deoxygenationis the elevation of intracellular free

MgH, they examined the dependenceof cell membrane fluctuations on intra-

cellular free MgH. Elevation of intracel-lular MgH in the high concentrationrange (0.8 mM) rigidified the red bloodcell. Anal;rsis of one aspect of thetransduction mechanism shows that

deoxygenation increases the level oftyrosine phosphorylation of band 3.When the rise in intracellular free MgHconcentration in deoxygenatedRBCsissimulated via clamping, the intracellularMg of oxygenatedRBCsby ionomycin,band 3 phosphorylation, is elevated byup to tenfold. These findings suggestthat the visco-elastic properties of hu-man erythrocytes may be regulated byMg-induced band 3 tyrosine phosphor-ylation 191.

Mg and the cardiovascular systemOr. Shechter with his Israeli and U.S.

colleagues studied 50 patients withstable coronary artery diseasewho par-ticipated in a supervisedcardiacexerciseprogram.Theywere randomizedinto twogroups: 25 patients received MgO tab-lets, 30 mmollday, and 25 receivedplacebo for 6 months. Thereafter, inorder to distinguish between the flow-mediated endothelium-dependent andthe endothelium-independentvasoreac-tivity of the brachial artery, the formerwas measuredusing 10 MHz ultrasono-graphy I hour and 30 min after occlusionof 3 min duration of the brachial arteryby means of a blood pressurecuff, andthe latter after administration of sub-lingual nitroglycerin. The flow-mediatedendothelium-dependent vasoreactivitywas significantly increased in the Mg-treated group (P < 0.02). The intracel-lular MgH was measured using X-raydispersion analysis of sublingual cells.The results suggestedthat Mg adminis-tration could benefit patientswith stablecoronary artery disease. In anotherstudy,a group of 49 patients with stablecoronary artery disease was examinedwith the samemethodology used in theprevious experiment in order to deter-

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mine whether increased intracellular

MgH level enhances brachial arteryreactivity.The flow-mediatedpercentagechange in the diameter of the brachialarterywas highly significantly associatedwith intracellular MgH content (P <0.00I), suggestinga role for Mg in thetreatment of stable coronary artery dis-ease1101.

Or. Schererand colleagueswho pre-viously showedthat a Mg-supplementeddiet modulated blood lipid levels andatherogenesis in the rabbit now usedIow density lipid receptor-deficientmiceand Mg~enriched drinking water. The

. experimental animals received eitherdistilled or Mg-enriched water and aIow cholesterol diet for 12 weeks fol-

lowed by 6 weekson a high cholesteroldiet. Mg, Ca and lipids were measured

. after12and 18weeksandthe extentofthe atheroscleroticchangesat the aorticsinus level was noted. The experimentalanimals given Mg-fortified water werefound to have a higher plasma Mgconcentration - the Ca content did notdiffer - and the extent of atherosclerotic

changeswas decreasedby two-thirds. Adecreaseoccurred even in the animals

thatwerefedahighcholesteroldiet 1111.

Mg in therapeuticsOr. Attias and his colleagues fromHumboldt University,Berlin, and theGermanFederalEnvironmentalAgency,reportedon the effectof Mg in preven-tion and treatmentof environmentallyinducedhearingloss.Exposureto highlevelnoiseaffectsabout 30%of indus-trial workers,excludingsoldiers.Sincemechanicalhearingprotectiondoesnotprovesufficientlyefficient.the effectofMg in prophylaxisof high level noise-inducedreductionof hearingwastestedin a. double-blind placebo-controlledstudy.A daily drinkcontaining167mgmagnesiumprovedto reducethe inci-denceof hearingloss, and a negativecorrelationbetweentheintensityofhighlevel noise and the Mg content oferythrocytesandmononuclearcellswasobserved.In anotherdouble-blindpla-cebo-controlledstudy, the temporarythreshold shifts and the oto-acousticcochlearemissionswerestudiedin hu-

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mans. Mg was foundto correlatewiththe oto-acousticcochlearemissionsand

to offer protection against TTS. LowerTTSand better cochlearstatus werealso

obtained in Mg-supplemented experi-mental animals,comparedwith controls.Moreover, histopathologic examinationestablishedthat the damageto cochlearouter hair cells was less in the Mg-supplementedanimals. Finally, ongoingstudiessuggestthat Mg mayalso haveatherapeutic effect once a reduction ofhearinglossoccurs1121.

Or. Onn and colleagues investigatedthe effectof Mg on asthma.A group of 26asthmatics (6 males and 5 females)including 16 severeand 10 mild cases,6 non-atopicand 20atopic cases,and (Iapparently healthy controls were inves-tigated for S-Mg, U-Mg, erythrocyteandmononuclearcell Mg content,and serumimmunoglobulin E level.Spirometryandskin prick test were carried out beforeand after a 4 hour Mg retention test. Thetest, consisting of infusion of 0.2 mg/kgof MgSO4,showed the presenceof Mgdeficiencyin 50%of the patients and in72%of the apparently healthy controls.In all asthmaticpatientsthe FEVl/ FVCratio increasedafter the infusion. U-Mgand erythrocyte Mg content were sig-nificantly increasedin non-atopic com-paredwith atopic patients, and in severeasthmatics compared with those withonly mild asthma (P < 0.05). In conclu-sion, all patients respondedto the briefMg infusion with bronchodilation. Theseverely ill asthmatics were more Mgdeficient than the milder cases,suggest-ing that Mg deficiency causesaggrava-tion of the disease.Thenon-atopiccaseswere more deficient than the atopicones, suggesting that Mg deficiencymay play a role in pathogenesisof non-atopic asthma 1131.

Or.Baharand Or.Bermanand collea-gues demonstrated how intrathecallyinjected MgSO4produces stable spinalanesthesia. In the first study, the intra-cellular concentrations of CaH, MgH,Na+ and K+of the thoracic and lumbar

spinal segments were measured after

TJ'S = temporary threshold shifts

MgSO4 anesthesiaandafter4%lidocaineinjection. Na+ and K+ concentrationsdecreased significantly I hour afterlidocaine injection and 24 hours afterMgSO4, whereasMgH concentrationrose only slightly after both injections.CaH concentrationrosesignificantly30and 60 min after MgSO4 injectionandremained elevated 24 hours later. Intra-cellular CaH concentration was signifi-cantly increased after 4% lidocaineinjection as well. A possible associationof thesechangeswith theactionofCaH

channels was discussed 1141.In the

second studXithe MgH, CaH, Na+ andK+content of blood mononuclearcellsof

experimental rats were measured afterintrathecalinjectionof 6.3%MgSO4or4% lidocaine solution. Na+ and K+concentrations increased 15 min after

lidocaine and 30 min after MgSO4injection, remaining elevated through-out a 24hourperiod.IntracellularMgHwas slightlyelevatedI hour after lido-caineand2hoursafterMgSO4injection.There were no significant changes inCaH concentration. The mononuclear

cells of the circulating blood appearedto be protected from the changesin thespinal cordcells that occurredasa resultof the intrathecal anesthesiainduced byMgSO4and lidocaine solutions respec-tively 1151.

Or. Mayanandcolleaguespresentedtwocasesofwomenwith eclampsiaandprematurelaborwhoreceivedMgtoco-lytic therapy.Ouringhypermagnesemiaresultingfrom the treatment,the pa-tients developedprolonged sympto-matic hypocalcemiaand undetectableparathyroidhormoneconcentration.Hereviewedthe fewsimilarcasesreportedpreviously in the literature and dis-cussedthe possiblecause.Heproposedthat since Mgwasan agonistfor thecalciumsensorreceptor,the latterwasinvolved in the developmentof thehypermagnesemia-inducedhypoca1-cemia1161.

Or.Stendig-Lindbergreportedon thecontinuationof an earlier 2 yearcon-trolled trial of oral Mg treatmentin 31postmenopausalosteoporoticwomenwho receivedtabletsof Mg(OHh,250-750 mg magnesiumper day, for 6

Israel Society for Research on Magnesium in Biology and Medicine 785

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I mO[1thsfollowedby 250 mg daily for 18months, Increase in bone density of 1-8%occurredin 71%of cases and arrest ofthe diseasein another16'7'0(MagnesRes

1993;6:155-63).Thus 89% (27 patients)responded and only 13% (4 patients)showed a decrease in bone density,Twoconsenting patients agreed to continuethe therapeutic trial beyond the 2 years,one a responder and the other a non-responder. They received 250 mg mag-nesium as Mg(OHbtablets daily, Bonedensity scan and laboratory screeningwere carried out periodicallyand theircompliance was checked, The bonedensity of one patient, aged 53, in-creased by 3%by the end of the 2 yeartriaLAfter8 years of follow-uptreatmenther bone density increased by 20%,reaching 108%of that in age-matchedand 93% in young female controls - atotal increase of 23%. The secondpatient, aged 56, showed no responseafter the controlled 2 year trial, but a14% increase after 2 years follow-uptreatment when her bone densityreached 109%of that in age-matchedand 92%in young female controls, Thevalue remained virtuallystationary dur-ing another 8 years, rising by a further2% two years later when the patientreached the age of 70 - a totalincrease of 16%.These findings illus-trate that adequate Mg intake leadingto a steady state of magnesium abol-ished menopausal osteoporosis andprevented the onset of senileosteoporosis 1171,

Acknowledgements. I wish to thank Prof. R,

Korenstein and Prof. R, Rahamimoff for

contributing a summary of their presenta-tions,

Referencesl. AikawaKJ.The Relationshipof Magne-

sium to Diseasein DomesticAnimals and

Humans, Springfield, USA: Charles C.Thomas, 1971.

2, Stendig-Lindberg G, Bergstrom I. Hult-man E, Hypomagnesaemiaand muscleelectrolytes and metabolites, Acta MedScand1977;20I:273-80,

3, Stendig-Lindberg G, Shapiro Y, Tepper-berg M, Moran D, Not only strenuousbutalso sustained moderate physical effort

causes magnesium deficiency,TraceEle-mentsElectrolytes1999;16:156-61.

4. Stendig-LindbergG, Moran D, Shapiro y,How significant is magnesiumin thermo-regulation? J BasicClin PhysiolPharmacal1998;9:73-85,

5, SeeligMS,The requirementof magne-sium by the normal adult. Summaryandanalysisof published data,Am JClin Nutr1964;14342-90,

6, Stendig-Lindberg G, Steady-state serumconcentration and therapeutic (target)concentration range during oral magne-sium therapy, Drug Invest]991;3:] 35-40,

7. SjogrenA, FlorenC-H, NilssonA Magne-sium and potassium status in healthysubjects as assessed by analysis ofmagnesium and potassium in skeletalmuscle biopsies and magnesium inmononuclear cells, MagnesExp Clin Res1987;6:91-9.

8 Stendig-Lindberg G, Harsat A, Graff E,

Magnesium content of mononuclear cells,

erythrocytes and 24-hour urine in carefully

screened apparently healthy Israelis, Eur JClin Chem Ctin Biochem 1991;30:833--6.

9, BarbulA: ZipserY,NachlesA: KorensteinR, Deoxygenationandelevationof intra-cellular magnesiuminducetyrosine phos-phorylation of band 3 in humanerythrocytes,FEBSLell 1999;455:87-91.

10, ShechterM, Sharir M, Paul-LabradorM,

ForresterI. BaireyMerzCN.Oral magne-sium therapy improves endothelial func-

tion in patients with coronary arterydisease,Circulation2000;102:2353-8,

11, Sherery, Schoenfeldy, ShaishA, Zevko-vitz H, Bitzur R, Harats D, Suppressionofatherogenesis in LDL-receptor deficientmice following magnesiumfortification ofdrinking water. MagnesRes2000;13:309.

12, Attias Y, Scheibe F, Ising H, Preventionand treatment of hearing loss bymagnesium, Magnes Res2000;13:309,

13, Onn A, Peretz-MorR,Stendig-LindbergG,Greiff I. Levo Y, Fireman E, Kivity S,

Magnesiuminvariousbodycompartmentsand asthma, Magnes Res2000;31 :3\ 0,

14, BaharM, BermanS,ChanimowM, Weiss-g~rten y, AverbukhZ, CohenML, Grinsh-pon y. Intrathecal anesthesia altersintracellular CaH/MgH homeostasis inthe spinal cord neurons of experimentalrats. Eur JAnaesth2001;18(4)231-7,

15. BaharM, BermanS,ChanimowM, Weiss-

garten Y,AverbukhZ, Cohen ML, Grinsh-pon y. Intracellular electrolyte homeo-stasis in rat peripheral blood mononuc-lear cells following intrathecal anaesthe-sia by magnesium sulfate or lidocaine,MagnesRes2000;13:311.

16. Mayan H, Hourwitz A, Schiff E, Farfel Z,Symptomatic hypocalcalcaemiain hyper-magnesaemia-induced hypoparathyroid-ism during magnesiumtocolytic therapy;possible involvement of the calciumsensor receptor,MagnesRes2000;13:31\,

17, Stendig-LindbergG, Long term oral mag-nesium treatment in postmenopausalosteoporosis. Abstracts of the SacklerFaculty of Medicine Research Fair, TelAviv University,April2001;T8:348,

Correspondence: Dr. G. Stendig-Lindberg,AssociateVisiting Professor,Dept. of Physiol-ogy and Pharmacology,Sackler Faculty ofMedicine, Tel Aviv University, Ramat Aviv69978, Israel.Phone:(972-3)642-9525,email: Iindberg@posUau.ac.il

Capsule .Connecting plaques and tangles .in Alzhei.Dler's,.ise.aControversy still rages over which of the two. hallmarkpathologies of Alzheimer'sdisease,amyloid plaques and tautangles, is the primary cause of neurodegeneration.in thebrain, '!\vo reports, by Lewis et aL and Gotzet aL, now showthat the two pathologies are not unconnected,Workingwith

786 G, Stendig-Lindberg

transgenic mice, the two grqupsthat beta-amyloid deposits information of tau tanglesin areas"ofaffected in Alzheimer'sdisease,

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